Colonic Mucosal Gene Expression and Genotype in Irritable Bowel Syndrome Patients

48 The mucosal gene expression in rectosigmoid mucosa (RSM) in irritable bowel syndrome 49 with diarrhea (IBS-D) is unknown. Our objectives were: first, to study mRNA expression (by 50 RT PCR of 19 genes pertaining to tight junctions, immune activation, intestinal ion transport 51 and bile acid homeostasis) in RSM in IBS-D patients (n=47) and healthy controls (n=17) and 52 study expression of a selected protein (PDZD3) in 10 IBS-D patients and 4 healthy controls; 53 second, to assess RSM mRNA expression according to genotype and fecal bile acid (BA) 54 excretion (high >2337mM/48h); and third, to determine whether genotype or mucosal mRNA 55 expression is associated with colonic transit or BA parameters. Fold changes were corrected for 56 false detection rate (FDR) for 19 genes studied (P<0.00263). In RSM in IBS-D patients 57 compared to controls, mRNA expression of GUC2AB, PDZD3, and PR2Y4 was increased, 58 whereas, CLDN1 and FN1 was decreased. One immune-related gene was upregulated (C4BP4) 59 and one downregulated (CCL20). There was increased expression of a selected ion transport 60 protein (PDZD3) on immunohistochemistry and Western blot in IBS-D compared to controls 61 (p=0.02) . There were no significant differences in mucosal mRNA in 20 IBS-D patients with 62 high, compared to 27 IBS-D patients with normal BA excretion. GPBAR1 (p<0.05) was 63 associated with colonic transit. We concluded that mucosal ion transport mRNA (for several 64 genes and PDZD3 protein) is upregulated and barrier protein mRNA downregulated in IBS-D 65 compared to healthy controls, independent of genotype. There are no differences in gene 66 expression in IBS-D with high compared to normal fecal BA excretion. 67